The two most common types of chronic wounds are venous ulcers (VUs) and diabetic ulcers (DUs). We will conduct the first double-blind randomized controlled trial (RCT) to test the effect of low-frequency, low- intensity (LFLI) ultrasound (US) on chronic wound healing and health related quality of life (HRQOL) with high statistical confidence (? < 0.05, power > 0.90, n=60 VUs, n=60 DUs). Our approach combines this active therapy with non-invasive diagnostic monitoring of wound hemodynamics throughout the treatment cycle, and includes analysis of the impact of nutritional status and inflammation on wound closure. There are several innovative aspects of this work. Specifically, (1) Our lightweight, battery-powered applicator is the first potentially wearable ultrasound wound therapy device that is safe to apply for extended periods of time. (2) The applicator actively promotes healing, which is fundamentally different from commercial ultrasonic systems that remove necrotic tissue only. (3) Our approach will link LFLI US exposure to changes in wound hemodynamics and HRQOL, which has the potential to enable personalized medicine. (4) Our analysis of patient nutritional and systemic inflammatory status may enable further treatment customization by identifying those patients most likely to benefit from LFLI US therapy. (5) Our approach incorporates both disease-specific and generic measures of HRQOL, which is unique for a therapeutic ultrasound RCT. Our low-frequency, low-intensity (20 kHz, <100 mW/cm2 spatial peak-temporal peak), portable ultrasound applicator is safe and clinically pragmatic wound treatment. The field lightweight (<25g) and permits parameters of our US device were previously optimized for venous ulcers, and our three recent pilot clinical human studies (VUs: n=20, n=25; DUs: n=10) demonstrated that our treatment improved healing by 15% per week compared to sham treatment. We therefore anticipate that our treatment will accelerate closure of chronic wounds, and we hypothesize that (1) LFLI US will improve generic and disease-specific HRQOL scores, (2) LFLI US will activate beneficial changes in the microvasculature of the wound and surrounding tissue, and (3) individuals with poor nutrition and high levels of inflammation will have delayed wound healing. Our specific aims are to: (1) Assess the effect of LFLI US on VUs and DUs by measuring wound closure as a primary endpoint and generic and disease-specific HRQOL as secondary endpoints. (2) Monitor the effects of LFLI US on wound perfusion and oxygenation using non-invasive optical methods, and (3) Determine the impact of nutritional status and inflammation on closure of DUs and VUs. Overall, this work will validate LFLI US as a safe, portable, and cost-effective therapy for chronic wounds. This is important because new therapies and improved clinical paradigms for wound management are urgently needed. Over the long-term, our findings may enable the development of personalized wound treatment regimens across care settings.